Natural killer (NK) cells display increased levels of pSTAT1 and the effector molecule TRAIL, an interferon-stimulated gene (ISG), indicating that they are chronically exposed to endogenous, HCV-induced type I interferon (IFN). Whether this NK cell phenotype is important for a response to antiviral therapy is unknown. Here we asked whether the NK cell phenotype pre-treatment and at early treatment time points differs between HCV-infected patients who develop a sustained virological response (SVR) to antiviral therapy (asunaprevir/daclatasvir or sofosbuvir/ledipasvir) and those who experience a virological breakthrough. Before treatment, patients who later achieved an SVR had a higher percentage of pSTAT1+ and TRAIL+ NK cells than those who later developed a virological breakthrough. This was accompanied by a higher frequency of degranulating (CD107a+) NK cells in response to target cells. Differential pSTAT1, TRAIL and CD107a expression in NK cells was maintained at day 1, and at week 2 or 4 of treatment even though HCV levels did not differ at those time points between patients who maintained their response to treatment and become sustained virological responders and patients who later developed a viral breakthrough. Thus, an enhanced IFN-signature is evident at pre-treatment and early on-treatment time points in NK cells of sustained virological responders compared to those that later develop a virological breakthrough. This is consistent with higher pretreatment expression levels of ISGs in sustained virological responders compared to those with viral breakthrough. Combined, the results suggest that an endogenous IFN response plays a role in preventing breakthrough. Antiviral therapy for hepatitis C can also be used to provide insights into the reversibility of chronic innate inflammatory responses and the potential for successful therapy to recover virus-specific memory immune responses. Effective therapy does not normalize all parts of the innate immune response, as shown for MAIT cells. MAIT cells are a population of innate-like T cells that is enriched at barrier sites such as liver and gut and activated by antigen (vitamin B metabolites displayed on non-classical MHC molecules) and by inflammatory cytokines (IL-12 and IL-18). Monocyte-derived IL-18 is increased in the HCV-infected liver, resulting in MAIT cell activation and reduction of peripheral and intrahepatic MAIT cells. Even though effective DAA therapy decreases intrahepatic activation of monocytes and plasma levels of IL18, followed by a decrease in MAIT cell activation and an increase in intrahepatic MAIT cell frequency, the frequency of MAIT cells in peripheral blood remains reduced for many months after the end of treatment and their antigen-dependent effector function is not restored. These findings indicate that decades of HCV infection have lasting effects on parts of the innate immune system, even after treatment-induced viral clearance.